The importance of providing dosage unit forms of medicinal agents for oral administration which release the drug slowly and at a uniform rate has long been recognized and has become more apparent as new drugs are made available. If the medicament is released too quickly, the stomach may become upset and the acid environment may have an adverse effect upon the drug. Sometimes the too rapid absorption of large amounts of potent drugs results in unnecessarily high blood levels of the drug which may, in turn, result in unpleasant side-effects or even toxic manifestations.
To ensure a controlled, long-lasting, continuous and not too intensive effective action of a therapeutic agent in the human body, it is necessary to be able to delay the absorption of the therapeutic agent by the body. This is especially important for water-soluble medicinal agents which are normally absorbed by the body fluids immediately after administration and consequently produce normally only a very short duration of effective action.
Many drugs such as potassium chloride for hypokalemia, aspirin, acetaminophen and ibuprofen for rheumatism, nicotinic acid for hypercholesteremia, theophyllin for the relief of bronchial asthma, griseofulvin for the treatment of conjunctivitis, corneal ulcer and antibiotics for fighting bacterial and viral infections, function best by maintaining the concentration of the medicament at the optimum therapeutic blood level. The traditional method of taking a capsule every few hours is often inconvenient and results in non-compliance by the patients.
As one example for the need for a dosage unit form which releases the drug at a relatively constant rate over a longer period of time, reference may be made to the treatment of hypokalemia with potassium salts such as potassium chloride, potassium bicarbonate, potassium citrate and potassium glycolate and others. In this treatment, relatively large amounts of potassium salts are given orally, often resulting in unpleasant side effects such as gastric ulceration, occasional bleeding and others. Analgesics and antiarthritic drugs when taken in large doses often give rise to similar undesirable side effects. Single smaller doses of antibiotics and antibacterial agents taken to fight infections have the desired therapeutic effect for no more than a few hours whereas large doses tend to result in severe abdominal cramping, upset stomach, vomiting, nausea, diarrhea and occasional hepatic dysfunction.
Up to now one of the methods commonly used in an attempt to provide prolonged duration of therapeutic agent is to mix the agent with insert waxy materials, e.g., calcium, magnesium and aluminium soap salts and/or other insoluble or partially soluble materials. This mass is then granulated using aqueous or non-aqueous solvents to provide granules, which are then compressed into tablets or pills. The sustained release effect is achieved when the tablet erodes or dissolves gradually in the gastrointestinal tract. This method is exemplified in U.S. Pat. Nos. 2,793,979, 3,065,143, 3,102,845, 3,184,386, 3,437,726 and 3,558,768.
The dosage form described above has a big disadvantage in that the tablet or pill travels through the intestinal tract as one large mass constantly in physical contact with gastrointestinal tissue, thereby causing intestinal and gastric ulceration, occasional bleeding and other undesirable side effects such as nausea, vomiting, epigastric distress and oval thrush.
Another commonly employed method for obtaining a so-called "prolonged" therapeutic effect from a pharmaceutical formulation is to coat a drug onto an innocuous core, e.g., nonpareil seeds (tiny sugar pellets) or onto drug crystals themselves. The thus coated drug pellets are then over-coated with several layers of retarding waxes or insoluble mixes in such fashion that, when filled into gelatin capsules, the release of the active drug from the capsule during its passage through the stomach and intestinal tract, is even and gradual. This method is exemplified in U.S. Pat. Nos. 3,383,283, 2,921,883, 3,365,365, 3,220,925 and 3,119,742.
Such a sustained release dosage form is limited, however, by the amount of coated beads or pellets that can be put into a size capsule that is convenient for swallowing. For example, a #1 hard gelatin capsule holds approximately 400 mg. of finished sustained release pellets and a #0 size capsule approximately 600 mg.
An examination of other prior art reveals numerous attempts to solve the problems defined above, with only limited success. None of the noted prior art employs my new inventive process and solution of the problem. For example, Press U.S. Pat. No. 2,953,497 describes a basic timed release composition and a method of preparing such composition. The patent describes therapeutically active ingredients which are coated on or mixed with a sugar/corn starch mixture to form granules. The therapeutically active ingredient-containing or coated granules are thereafter coated with shellac and/or a cellulose acetate phthalate solution to reduce the rate of release of the therapeutically active ingredient. The patent does not disclose my method of forming a tablet containing disintegrant-coated medicament-containing controlled release particles or such a tablet itself.
Barry U.S. Pat. No. 2,996,431 is directed to a procedure for making a friable tablet and the tablet produced thereby. According to the patent, the tablet can be broken into small sized particles by application of the pressure of the thumb or other finger on the tablet against a surface, such as that of a table, in a single operation. The tablet is composed of granules or spheroidal pellets composed of sugar/corn starch with a coating of medicinal agent. The medicinal agent-containing pellets are then coated with, inter alia, shellac or cellulose esters, such as the acetate and acetate phthalate. The granules or pellets are then incorporated in a matrix or binder and pressed into the desired shape. The patent does not describe my use of a thin, uniform coating of a disintegrant on a medicament containing pellet, nor my process of forming a compressed tablet containing such disintegrant-coated pellets.
Halley U.S. Pat. No. 3,044,938 describes a sustained action pharmaceutical tablet and a process of making the same. The disclosure indicates that at least some portions of a medicament incorporate an ingredient which simultaneously functions as an "action-retardant" and as a binder. By including a plurality of such special action-retarding and binding ingredients into the same tablet or by incorporating action-retarding and binding ingredients and medicament in unaltered form, sustained-release action may be obtained. The patent does not, however, describe my process, or a tablet formed thereby, in which retarded or coated pellets of medicament are further coated with a layer of disintegrants prior to compressing the tablet.
Hermelin U.S. Pat. No. 3,115,441 discloses timed release tablets in which a.plurality of small particles of an analgesic drug coated with a solution-resistant coating is dispersed throughout a compressed matrix including particles of the same analgesic drug in uncoated form. There is no discussion in the patent of my use of disintegrants, nor of my process for forming disintegrant-coated medicament-containing particles in a compressed tablet.
Berger U.S. Pat. No. 3,344,029 describes a sustained release preparation which includes a plurality of resilient cores, each of which is formed from a cohesive intimate mixture of finely divided, therapeutically active material in powder form and an ingestible material which is resistant to disintegration in the gastrointestinal tract. A portion of the core is coated with alternating coatings of therapeutically active materials and ingestible material. The patent does not disclose the use of a disintegrant layer on a sustained release medicament-containing particle, nor a compressed tablet including a plurality of such disintegrant-coated particles, as my invention describes.
Noyes U.S. Pat. No. 536,155, Mori et al. Japanese Patent Publication No. 53-127,821, and Wilen U.S. Pat. No. 2,297,599 disclose various forms of coated particles of medicament but they do not describe my uniform coating of a retarding material on a medicament-containing particle overlaid with a uniform coating of disintegrant material and then compressed into a dense tablet that breaks up quickly in the body.